In patients with neurological or psychiatric disorders, e.g. Parkinson's disease, essential tremor, dystonia, functional disorders after stroke, migraine, obsessive-compulsive disorders, epilepsy, tinnitus, schizophrenia, depression, borderline personality disorder and irritable bowel syndrome, nerve cell clusters in distinct regions of the brain are active in a pathologically synchronous manner. In this case, a large number of neurons synchronously form action potentials, i.e. the involved neurons fire in an excessively synchronous manner. In healthy persons, however, the neurons in these brain regions fire qualitatively differently, e.g. in an uncorrelated manner.
In Parkinson's disease, the pathologically synchronous activity in the thalamus and in the basal ganglia changes the neuronal activity in other brain regions, e.g. in areas of the cerebral cortex, such as the primary motor cortex. Here, the pathologically synchronous activity in the region of the thalamus and of the basal ganglia enforces its rhythm e.g. on the cerebral cortex areas, so that finally the muscles controlled by these areas display a pathological activity, e.g. a rhythmic trembling (tremor). In the case of a chronic subjective tinnitus, pathologically synchronous activity is found in a network of auditory and non-auditory brain areas.
In patients with brain diseases and spinal cord diseases, which are characterized by excessively synchronized neuronal activity, non-invasively determined spatiotemporal stimulus patterns, in particular the “coordinated reset” stimulation (CR stimulation), are applied in order to achieve permanent alleviation. The non-invasive CR stimulation can be realized by means of different stimulation modes:
(i) by sensory stimulation, i.e. by physiological stimulation of receptors, such as e.g. acoustic stimulation of the inner ear, visual stimulation of the retina or mechanical (e.g. vibrotactile) or thermal stimulation of skin, subcutaneous, muscle and tendon receptors;(ii) by stimulation of peripheral nerves (and associated receptors), e.g. by means of electric current (e.g. transcutaneous electrical stimulation), by means of magnetic fields (transdermal magnetic stimulation) or by means of ultrasound; and(iii) by stimulation of the brain or spinal cord, e.g. by means of electric current (e.g. external cranial or transcranial neurostimulation), by means of magnetic fields (e.g. transcranial magnetic stimulation) or by means of ultrasound.
Acoustic CR stimulation is used to treat the chronic subjective tonal or narrow-band tinnitus. To this end, therapy tones are adapted to the dominant tinnitus tone and are applied for the purpose of CR stimulation in order to achieve a long-lasting desynchronization of the pathologically synchronous activity, which significantly exceeds the switch-off of the stimulation, or even a continuous desynchronization thereof. Acoustic CR stimulation for treating tinnitus brings about a significant and clearly marked reduction of symptoms (cf. P. A. Tass, I. Adamchic, H.-J. Freund, T. von Stackelberg, C. Hauptmann: Counteracting tinnitus by acoustic coordinated reset neuromodulation. Restorative Neurology and Neuroscience 30, 137-159 (2012)), a significant reduction in the pathological neuronal synchronization in a network of auditory and non-auditory brain areas (cf. P. A. Tass, I. Adamchic, H.-J. Freund, T. von Stackelberg, C. Hauptmann: Counteracting tinnitus by acoustic coordinated reset neuromodulation. Restorative Neurology and Neuroscience 30, 137-159 (2012); I. Adamchic, T. Toth, C. Hauptmann, P. A. Tass: Reversing pathologically increased EEG power by acoustic CR neuromodulation. Human Brain Mapping 35, 2099-2118 (2014)), a significant reduction in the pathological interactions between different brain areas in the same (cf. A. N. Silchenko, I. Adamchic, C. Hauptmann, P. A. Tass: Impact of acoustic coordinated reset neuromodulation on effective connectivity in a neural network of phantom sound. Neuroimage 77, 133-147 (203)) as well as in different (cf. Adamchic, B. Langguth, C. Hauptmann, P. A. Tass: Abnormal brain activity and cross-frequency coupling in the tinnitus network. Frontiers in Neuroscience 8, 284 (2014)) frequency ranges.
In an analogous manner, Parkinson's disease can be treated by means of vibrotactile CR stimulation. Further indications are, for example, epilepsy, functional disorders after stroke, chronic pain syndromes (by means of vibrotactile and/or thermal CR stimulation), migraine (e.g. by means of visual CR stimulation). Furthermore, these diseases can be treated with transcranial magnetic stimulation or direct electrical stimulation of the brain or direct brain stimulation by means of ultrasound.
In all three above-mentioned stimulation modalities (i) to (iii), low stimulus intensities should be used for stimulation in order to avoid disadvantages (for different reasons described in the following). However, this should not lead to a reduction in the effectiveness of the stimulation nor to an extension of the stimulation duration.
(i) Sensory stimulation: In sensory stimulation, it is important that the desired stimulation effects, e.g. a phase resetting of the pathologically synchronized oscillatory activity in the brain or spinal cord, can be achieved at all with the lowest possible stimulus intensity. For example, in acoustic CR stimulation for the treatment of tinnitus, typically hearing-impaired patients have to be treated. Stimulation with loud tones can damage the inner ear, can make a communication with others more difficult, and can cover warning sounds such as a vehicle horn or bicycle bell, or can be perceived as clearly unpleasant by the patient as a result of the intolerability threshold being comparatively close to the hearing threshold. The acoustic stimulation of tinnitus patients with hyperacusis can be particularly problematic, since such patients perceive acoustic stimulation partly as unpleasant or even unbearable. In addition, in the case of hearing-impaired tinnitus patients, the loud stimulation can also be heard and be perceived as disturbing by the patient's environment. In the visual CR stimulation, unpleasant glare effects can occur in particular in the case of migraine patients. In the case of a mechanical, e.g. vibrotactile or thermal CR stimulation of patients with chronic pain syndromes, e.g. with Sudeck's disease or neuralgias, even slight touching or thermal stimuli can be perceived as unpleasant or even painful. If, in such cases, treatment has to occur via the contralateral extremity or face or body half, the stimulatory effect is not strongly pronounced as a result of the application in the healthy body half. All in all, it is very advantageous in sensory CR stimulation if very low stimulus intensities can be used for stimulation, since sensory stimuli, such as tones, brightness fluctuations of transmission glasses, etc. can interfere with the physiological stimulus processing.
(ii) Electrical or magnetic stimulation of peripheral nerves: In order to be able to stimulate as focally as possible and to prevent side effects that are caused by the simultaneous stimulation of adjacent structures, e.g. muscle contractions, pain sensations, etc., it is important that the smallest possible stimulus intensities be used.
(iii) Electrical or magnetic stimulation of the brain or spinal cord: Both stimulation forms are not very focal. For example, even in the most favorable case of stimulation via a plurality of small electrodes and when using complex head models, in addition to a strong focal stimulation, direct electrical stimulation of the brain leads to an accompanying stimulation of far-stretched brain regions, which should be avoided or reduced particularly in the case of chronic irritation. In the same way, ultrasonic stimulation should be limited to the actual target regions in the brain.
In all of these cases, it is therefore necessary to be able to perform the treatment with the smallest possible stimulus intensities in order to reduce the undesired simultaneous stimulation of non-target areas. However, this often leads to the fact that the treatment is not sufficiently effective.